Anthracycline antibiotics, especially daunorubicin and doxorubicin have important therapeutic efficacy against acute leukemias and a variety of neoplasms including a number of solid tumors. As with most antineoplastic chemotherapeutic agents, the anthracycline antibiotics exhibit a number of toxic manifestations including bone marrow depression, stomatitis, alopecia, gastrointestinal disturbances and sometimes dermatological mainifestations. In addition, cardiac toxicity is a unique adverse characteristic of anthracycline antibiotics. Two forms of cardiac toxicity have been observed: (1) an acute form characterized by abnormal ECG changes including ST-T alterations and arrhythmias; and (2) chronic, cumulative dose-related toxicity characterized by congestive heart failure unresponsive to digitalis. In sum, cardiac toxicity is manifested by tachycardia, arrhythmias, dyspnea, hypotension and congestive heart failure which does not respond to digitalis. The cumulative, dose-limiting cardiotoxicity is a major obstacle to the therapeutic use of the anthracycline antibiotics.
Thus, there has been a long-felt need for analogs and/or derivatives of anthracycline antibiotics which maintain therapeutic efficacy against neoplasms but have diminished or eliminated cardiotoxicity. For a general review of derivatives of anthracycline antibiotics that have been developed with a view to lowering cardiotoxicity, see Weiss et al., 1986, Cancer Chemother. Pharmacol 18:185-97 and references cited therein.
In an attempt to prepare anthracycline antibiotic derivatives to serve as prodrugs which would be selective substrates for the enzyme plasmin which is often found in elevated levels at solid tumor sites, Chakravarty et al., (1983, J. Med. Chem. 26:638-44) synthesized 3' peptidyl derivatives of doxorubicin. For example, 3'-(D-val-L-leu-L-lys)-doxorubicin was obtained using a mixed anhydride of the protected FMOC-peptide in isobutyl chloroformate followed by removal of the FMOC group using anhydrous ammonia.
Other investigators have prepared C-13 bis-hydrazone derivatives of anthracycline antibiotics. For example, U.S. Pat. No. 4,112,217 issued to Henry et al. describes C-13 bis-hydrazone derivatives of doxorubicin and daunorubucin formed by reacting an excess molar amount of either doxorubicin or daunorubicin with an acid hydrazide. More recently, Brownler et al. (1986, J. Chem. Soc. Chem. Comm. 1986:659-61) describes synthesis of a mono-hydrazone adduct of daunorubicin having a free hydrazide moiety which was formed by reaction of daunorubicin hydrochloride and a dihydrazide of the formula ##STR1##